Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients

E Vandemeulebroucke, B Keymeulen, K Decochez, I Weets, C De Block, F Féry, U Van de Velde, I Vermeulen, P De Pauw, C Mathieu, D G Pipeleers, F K Gorus, Belgian Diabetes Registry, P Abrams, C Algoet, P Arnouts, S Ayoubi, A Bachy, J Baeyens, E Balasse, G Bataille, D Beckers, V Beckers, H Becq, A Beirinckx, J Beirinckx, M Bex, A Bocquet, A Bodson, F Bosly, H Bossaert, R Bouillon, M S Bouquegneau, J Bourguignon, H Brussaard, M Buysschaert, M Cardon, A Carlier, K Casteels, E Cavatorta, A Chachati, A Claessens, C Claeys, L Claeys, M Claeys, M Cnop, P Cochez, M Coeckelberghs, V Col, M Colin, J L Coolens, P Coremans, B Corvilain, F Coucke, W Coucke, E Couturier, A Crapé, L Crenier, P Damoiseaux, N Daoudi, C Daper, C Daubresse, J C Daubresse, M De Backer, C De Block, I De Feyter, E De Groot, R De Hauwere, K De Keyser, I De Leeuw, J De Schepper, K De Schynkel, K De Waele, G De Wasch, J A Decerf, K Decochez, P Decraene, F Defoer, R Demaeseneer, L Derdelinckx, S Deweer, L Dooms, H Dorchy, S Driessens, M Du Caju, J Ducobu, V Dumasy, E Duvivier, F Duyck, A Dysseleer, L Emsens, W Engelen, C Ernould, V Ers, C Evenepoel, A Eykens, N Favere, F Fery, R Fils, L Frankart, N Gaham, E Galopin-Vanderstappen, K Garmijn, J Gerard, I Geronooz, P Gillard, C Gillet, M Giri, F Gorus, J Guiot, A Haemers, S Haemers, C Hendrieckx, C Herbaut, G Heremans, F Heureux, E Heyns, R Hilbrands, A Huard, G Hubermont, J Huyghe, V Immegeers, B Jandrain, P Jopart, J Kaufman, B Keymeulen, M Kin-Willems, P Kleynen, Y Kockaerts, G Krzentowski, K Laga, E Lagasse, G Lamberigts, E Lambrecht, M C Lebrethon, P Lefebvre, F Lienart, T Lim Tjin, C Litvine, K Logghe, J Louis, M Maes, W Maes, M Marchal, P Marien, G Massa, C Mathieu, Z Mathijs, D Mattelaer, Y Maus, K Mekeirele, F Merahli, J Mockel, J Monballyu, G Moorkens, T Moureau, E Muls, W Musch, P Nachtegaele, K Naudts, I Neven, D Nicolaij, F Nobels, A Nollet, F Paciorkowski, N Paquot, I Paris, C Peeters, F Peiffer, M C Pelckmans, H Penninckx, O Peters, J C Philips, M Pieron, D Pipeleers, K Platteau, L Poelmans, M Ponchon, A Purnode, C Remy, B Renneboog, C Righes, D Rocour-Brumioul, M P Roggemans, R Rooman, R Rottiers, J Ruige, D Scarniere, A Scheen, E Schils, I Schoemaker, L Schrijvers, M Schuerman, J Schutyser, P Selvais, N Seret, K Spincemaille, M P Stassen, M Strivay, M Struelens, P Taelman, S Tenoutasse, L Terriere, J Teuwen, G Thenaers, G Thiry-Counson, J Tits, G Tsibuabua, G Tsjoen, C Tuyttens, J Unger, K Van Acker, E Van Aken, S Van Aken, P Van Belle, P Van Crombrugge, A Van Den Bruel, J Van Den Saffele, B Van der Auwera, J Van Doorn, E Van Fleteren, L Van Gaal, L Van Garsse, D Van Gijsegem, M Van Helvoirt, S Van Imschoot, E Van Kerchove, C Van Parijs, I Van Pottelbergh, P Van Rooy, C Van Winghem, J Vanbesien, X Vande Mergel, H Vandecauter, E Vandemeulebroucke, M Vandenbroucke, E Vandenbussche, A Vandergheynst, M Vanderijst, H Vanderstappen, G Vanhaverbeke, S Vanneste, D Vannimmen, J Vanuytsel, R Verbiest, C Vercammen, P Vergauwe, A Verhaegen, G Verhaert, V Verjans, R Verniest, J Verschuere, B Vets, G Vieillevoye, J Vinckx, S Vinken, C Warnotte, P Watillon, E Weber, I Weemaes, I Weets, L Winne, E Vandemeulebroucke, B Keymeulen, K Decochez, I Weets, C De Block, F Féry, U Van de Velde, I Vermeulen, P De Pauw, C Mathieu, D G Pipeleers, F K Gorus, Belgian Diabetes Registry, P Abrams, C Algoet, P Arnouts, S Ayoubi, A Bachy, J Baeyens, E Balasse, G Bataille, D Beckers, V Beckers, H Becq, A Beirinckx, J Beirinckx, M Bex, A Bocquet, A Bodson, F Bosly, H Bossaert, R Bouillon, M S Bouquegneau, J Bourguignon, H Brussaard, M Buysschaert, M Cardon, A Carlier, K Casteels, E Cavatorta, A Chachati, A Claessens, C Claeys, L Claeys, M Claeys, M Cnop, P Cochez, M Coeckelberghs, V Col, M Colin, J L Coolens, P Coremans, B Corvilain, F Coucke, W Coucke, E Couturier, A Crapé, L Crenier, P Damoiseaux, N Daoudi, C Daper, C Daubresse, J C Daubresse, M De Backer, C De Block, I De Feyter, E De Groot, R De Hauwere, K De Keyser, I De Leeuw, J De Schepper, K De Schynkel, K De Waele, G De Wasch, J A Decerf, K Decochez, P Decraene, F Defoer, R Demaeseneer, L Derdelinckx, S Deweer, L Dooms, H Dorchy, S Driessens, M Du Caju, J Ducobu, V Dumasy, E Duvivier, F Duyck, A Dysseleer, L Emsens, W Engelen, C Ernould, V Ers, C Evenepoel, A Eykens, N Favere, F Fery, R Fils, L Frankart, N Gaham, E Galopin-Vanderstappen, K Garmijn, J Gerard, I Geronooz, P Gillard, C Gillet, M Giri, F Gorus, J Guiot, A Haemers, S Haemers, C Hendrieckx, C Herbaut, G Heremans, F Heureux, E Heyns, R Hilbrands, A Huard, G Hubermont, J Huyghe, V Immegeers, B Jandrain, P Jopart, J Kaufman, B Keymeulen, M Kin-Willems, P Kleynen, Y Kockaerts, G Krzentowski, K Laga, E Lagasse, G Lamberigts, E Lambrecht, M C Lebrethon, P Lefebvre, F Lienart, T Lim Tjin, C Litvine, K Logghe, J Louis, M Maes, W Maes, M Marchal, P Marien, G Massa, C Mathieu, Z Mathijs, D Mattelaer, Y Maus, K Mekeirele, F Merahli, J Mockel, J Monballyu, G Moorkens, T Moureau, E Muls, W Musch, P Nachtegaele, K Naudts, I Neven, D Nicolaij, F Nobels, A Nollet, F Paciorkowski, N Paquot, I Paris, C Peeters, F Peiffer, M C Pelckmans, H Penninckx, O Peters, J C Philips, M Pieron, D Pipeleers, K Platteau, L Poelmans, M Ponchon, A Purnode, C Remy, B Renneboog, C Righes, D Rocour-Brumioul, M P Roggemans, R Rooman, R Rottiers, J Ruige, D Scarniere, A Scheen, E Schils, I Schoemaker, L Schrijvers, M Schuerman, J Schutyser, P Selvais, N Seret, K Spincemaille, M P Stassen, M Strivay, M Struelens, P Taelman, S Tenoutasse, L Terriere, J Teuwen, G Thenaers, G Thiry-Counson, J Tits, G Tsibuabua, G Tsjoen, C Tuyttens, J Unger, K Van Acker, E Van Aken, S Van Aken, P Van Belle, P Van Crombrugge, A Van Den Bruel, J Van Den Saffele, B Van der Auwera, J Van Doorn, E Van Fleteren, L Van Gaal, L Van Garsse, D Van Gijsegem, M Van Helvoirt, S Van Imschoot, E Van Kerchove, C Van Parijs, I Van Pottelbergh, P Van Rooy, C Van Winghem, J Vanbesien, X Vande Mergel, H Vandecauter, E Vandemeulebroucke, M Vandenbroucke, E Vandenbussche, A Vandergheynst, M Vanderijst, H Vanderstappen, G Vanhaverbeke, S Vanneste, D Vannimmen, J Vanuytsel, R Verbiest, C Vercammen, P Vergauwe, A Verhaegen, G Verhaert, V Verjans, R Verniest, J Verschuere, B Vets, G Vieillevoye, J Vinckx, S Vinken, C Warnotte, P Watillon, E Weber, I Weemaes, I Weets, L Winne

Abstract

Aims/hypothesis: The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients.

Methods: Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT.

Results: Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp.

Conclusions/interpretation: Clamp-derived functional variables stratify risk of diabetes in IA-2A(+) FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage.

Trial registration: ClinicalTrials.gov NCT00654121

Funding: The insulin trial was financially supported by Novo Nordisk Pharma nv.

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